N-acetylcysteine supplementation remodels thiol-related biochemical pathways towards decreased oxidation in diabetic submandibular glands





Diabetes Mellitus; Submandibular gland; Oxidative stress; N-acetylcystein.


Secondary disorders in consequences to diabetes involves the development of several diseases in the oral cavity, as periodontitis, xerostomy, infection by diverse pathogens and dysfunctions on the salivary secretion. These alterations occur partially, in consequence of the oxidative stress occasioned by hyperglycemia, and are important in patients undiagnosed or that have flaws in their therapeutic process. The aim of this work was to evaluate biochemical alterations of submandibular glands in response to oxidative stress during diabetes mellitus, and verify the effects of N-acetylcystein supplementation to diabetic rats, specially on the regulation of modifications related to glutathione and thiol proteins. For this purpose, the levels of some oxidative stress markers and the occurrence of the post-translational event of S-glutathionylation were evaluated. The a-amilase degranulation by isolated acinar cells and glandular relative weight was also measured for each experimental group. The compound was able to decrease the lipoperoxidation and proteic oxidation observed in the submandibular gland of diabetic rats, preventing the decrease of the tecidual reducing power and increasing the occurrence of the post-translational process of S-glutathionylation. The diabetic condition increases the degranulation of a-amilase and the glandular weight, but the supplementation with N-acetylcystein did not affect these events. Together these findings may help to elucidate the status of oxidative stress on salivary glands and suggest new therapeutic strategies employing antioxidants of low molecular weight to prevent oral and systemic dysfunctions related to diabetes.


Anderson, L. C., Suleiman, A. H., & Garrett, J. R. (1994). Morphological effects of diabetes on the granular ducts and acini of the rat submandibular gland. Microscopy research and technique, 27(1), 61-70.

Anderson, L. C., Yang, S. C., Xie, H., & Lamont, R. J. (1994). The effects of streptozotocin diabetes on salivary-mediated bacterial aggregation and adherence. Archives of oral biology, 39(4), 261-269.

Aruoma, O. I., Halliwell, B., Hoey, B. M., & Butler, J. (1989). The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radical Biology and Medicine, 6(6), 593-597.

Atli, T., Keven, K., Avci, A., Kutlay, S., Turkcapar, N., Varli, M., …& Canbolat, O. (2004). Oxidative stress and antioxidant status in elderly diabetes mellitus and glucose intolerance patients. Archives of gerontology and geriatrics, 39(3), 269-275.

Bradford, M.M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical biochemistry, 72(7), 248-54.

Brigagão, M. R. P. L. (2004). Estudo do processo de S-glutationação protéica no BURST respiratório de leucócitos: modulação pela lactona sesquiterpênica licnofolido (Doctoral dissertation, Universidade de São Paulo).

Caylak, E., Aytekin, M., & Halifeoglu, I. (2008). Antioxidant effects of methionine, α-lipoic acid, N-acetylcysteine and homocysteine on lead-induced oxidative stress to erythrocytes in rats. Experimental and Toxicologic Pathology, 60(4-5), 289-294.

Choi, S. W., Benzie, I. F., Ma, S. W., Strain, J. J., & Hannigan, B. M. (2008). Acute hyperglycemia and oxidative stress: direct cause and effect?. Free Radical Biology and Medicine, 44(7), 1217-1231.

Dohi, T., Kawamura, K., Morita, K., Okamoto, H., & Tsujimoto, A. (1988). Alterations of the plasma selenium concentrations and the activities of tissue peroxide metabolism enzymes in streptozotocin-induced diabetic rats. Hormone and metabolic research, 20(11), 671-675.

Dominguez, A., Ramos-Morales, F., Romero, F., Rios, R. M., Dreyfus, F., Tortolero, M., & Pintor-Toro, J. A. (1998). hpttg, a human homologue of rat pttg, is overexpressed in hematopoietic neoplasms.

Evidence for a transcriptional activation function of hPTTG. Oncogene, 17(17), 2187-2193.

Ercal, N., Aykin-Burns, N., Gurer-Orhan, H., & McDonald, J. D. (2002). Oxidative stress in a phenylketonuria animal model. Free Radical Biology and Medicine, 32(9), 906-911.

Esterbauer, H., & Cheeseman, K. H. (1990). Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods in enzymology, 186, 407-421.

Ezeriņa, D., Takano, Y., Hanaoka, K., Urano, Y., & Dick, T. P. (2018). N-acetyl cysteine functions as a fast-acting antioxidant by triggering intracellular H2S and sulfane sulfur production. Cell chemical biology, 25(4), 447-459.

Feillet-Coudray, C., Rock, E., Coudray, C., Grzelkowska, K., Azais-Braesco, V., Dardevet, D., & Mazur, A. (1999). Lipid peroxidation and antioxidant status in experimental diabetes. Clinica Chimica Acta, 284(1), 31-43.

Godin, D. V., Wohaieb, S. A., Garnett, M. E., & Goumeniouk, A. D. (1988). Antioxidant enzyme alterations in experimental and clinical diabetes. Molecular and cellular biochemistry, 84(2), 223-231.

Heydari, I., Radi, V., Razmjou, S., & Amiri, A. (2010). Chronic complications of diabetes mellitus in newly diagnosed patients. International Journal of Diabetes Mellitus, 2(1), 61-63.

Kakkar, R., Kalra, J., Mantha, S. V., & Prasad, K. (1995). Lipid peroxidation and activity of antioxidant enzymes in diabetic rats. Molecular and cellular biochemistry, 151(2), 113-119.

Klatt, P., & Lamas, S. (2000). Regulation of protein function by S‐glutathiolation in response to oxidative and nitrosative stress. European journal of biochemistry, 267(16), 4928-4944.

Lii, C. K., Chai, Y. C., Zhao, W., Thomas, J. A., & Hendrich, S. (1994). S-thiolation and irreversible oxidation of sulfhydryls on carbonic anhydrase III during oxidative stress: a method for studying protein modification in intact cells and tissues. Archives of biochemistry and biophysics, 308(1), 231-239.

Limaye, P. V., Raghuram, N., & Sivakami, S. (2003). Oxidative stress and gene expression of antioxidant enzymes in the renal cortex of streptozotocin-induced diabetic rats. Molecular and cellular biochemistry, 243(1), 147-152.

Liu, Y., Zhang, H., Zhang, L., Zhou, Q., Wang, X., Long, J., ... & Zhao, W. (2007). Antioxidant N-acetylcysteine attenuates the acute liver injury caused by X-ray in mice. European journal of pharmacology, 575(1-3), 142-148.

Mills, B. J., & Lang, C. A. (1996). Differential distribution of free and bound glutathione and cyst (e) ine in human blood. Biochemical pharmacology, 52(3), 401-406.

Miranda Filho, A. E. de F., Silva, A. B. ., Apolicauto , Érica ., Lopes, G. D. S.., Rodrigues, P. R. ., Neves, T. V. B. ., Veloso, R. B. ., Garcia, J. A. D. ., Salles, B. C. C. ., & Santos, G. B. . (2021). Atividade do extrato hidroetanólico das folhas de Raphanus Sativus em glândulas submandibulares de ratos com diabetes mellitus. Research, Society and Development, 10(2), e21610212447. https://doi.org/10.33448/rsd-v10i2.12447

Nogueira, F. N., dos Santos, M. F., & Nicolau, J. (2005). Influence of streptozotocin-induced diabetes on hexokinase activity of rat salivary glands. Journal of physiology and biochemistry, 61(3), 421.

Pasupathi, P., Chandrasekar, V., & Kumar, U. S. (2009). Evaluation of oxidative stress, enzymatic and non-enzymatic antioxidants and metabolic thyroid hormone status in patients with diabetes mellitus. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 3(3), 160-165.

Pedraza-Chaverrí, J., Barrera, D., Medina-Campos, O. N., Carvajal, R. C., Hernández-Pando, R., Macías-Ruvalcaba, N. A., ... & Ibarra-Rubio, M. E. (2005). Time course study of oxidative and nitrosative stress and antioxidant enzymes in K 2 Cr 2 O 7-induced nephrotoxicity. BMC nephrology, 6(1), 1-12.

Pereira A.S. et al. (2018). Metodologia da pesquisa científica. [eBook]. Santa Maria. Ed. UAB / NTE / UFSM.

Pocernich, C. B., La Fontaine, M., & Butterfield, D. A. (2000). In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain. Neurochemistry international, 36(3), 185-191.

Qujeq, D., Aliakbarpour, H. R., & Kalavi, K. (2004). Relationship between malondialdehyde level and glutathione peroxidase activity in diabetic rats. Clinica Chimica Acta, 340(1-2), 79-83.

Rahman, S., Rahman, T., Ismail, A. A. S., & Rashid, A. R. A. (2007). Diabetes‐associated macrovasculopathy: pathophysiology and pathogenesis. Diabetes, Obesity and Metabolism, 9(6), 767-780.

Reznick, A. Z., Shehadeh, N., Shafir, Y., & Nagler, R. M. (2006). Free radicals related effects and antioxidants in saliva and serum of adolescents with Type 1 diabetes mellitus. Archives of oral biology, 51(8), 640-648.

Sampathkumar, R., Balasubramanyam, M., Sudarslal, S., Rema, M., Mohan, V., & Balaram, P. (2005). Increased glutathionylated hemoglobin (HbSSG) in type 2 diabetes subjects with microangiopathy. Clinical biochemistry, 38(10), 892-899.

Sandberg, G. E., Sundberg, H. E., Fjellstrom, C. A., & Wikblad, K. F. (2000). Type 2 diabetes and oral health: a comparison between diabetic and non-diabetic subjects. Diabetes research and clinical practice, 50(1), 27-34.

Saxena, A. K., Srivastava, P., Kale, R. K., & Baquer, N. Z. (1993). Impaired antioxidant status in diabetic rat liver: effect of vanadate. Biochemical pharmacology, 45(3), 539-542.

Seghrouchni, I., Drai, J., Bannier, E., Rivière, J., Calmard, P., Garcia, I., ... & Revol, A. (2002). Oxidative stress parameters in type I, type II and insulin-treated type 2 diabetes mellitus; insulin treatment efficiency. Clinica Chimica Acta, 321(1-2), 89-96.

Soell, M., Hassan, M., Miliauskaite, A., Haikel, Y., & Selimovic, D. (2007). The oral cavity of elderly patients in diabetes. Diabetes & metabolism, 33, S10-S18.

Wohaieb, S. A., & Godin, D. V. (1987). Alterations in free radical tissue-defense mechanisms in streptozocin-induced diabetes in rat: effects of insulin treatment. Diabetes, 36(9), 1014-1018.

Yuen, H. K., Wolf, B. J., Bandyopadhyay, D., Magruder, K. M., Salinas, C. F., & London, S. D. (2009). Oral health knowledge and behavior among adults with diabetes. Diabetes research and clinical practice, 86(3), 239-246.




How to Cite

MIRANDA FILHO, A. E. de F.; RIBEIRO, A. C. G. .; NUNES, N. F. M. L. .; LIMA, S. N. P. .; ROCHA, V. F. B. .; LAURINDO, F. R. M. .; SANTOS, G. B. .; BRIGAGÃO , M. R. P. L. . N-acetylcysteine supplementation remodels thiol-related biochemical pathways towards decreased oxidation in diabetic submandibular glands. Research, Society and Development, [S. l.], v. 10, n. 3, p. e14510313169, 2021. DOI: 10.33448/rsd-v10i3.13169. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/13169. Acesso em: 12 apr. 2021.



Health Sciences